Therapies for acute myeloid leukemia in patients ineligible for standard induction chemotherapy: a systematic review.

Aim: To review clinical evidence for current and emerging treatments for patients with acute myeloid leukemia (AML) who are ineligible for first-line induction chemotherapy. Methods: A systematic literature review was performed (28 October 2021) to identify clinical outcomes including overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) and adverse events (AEs). Results: Of 233 references that met prespecified criteria, 26 studies were included. Adding targeted therapies (venetoclax/ivosidenib) to hypomethylating agents (HMAs) yielded better OS hazard ratios (HRs) (0.44-0.66) and EFS HRs (0.33-0.63) compared with other agents. AEs were more frequent with combination therapies than control arms, except with ivosidenib plus azacitidine. Conclusion: Targeted therapy combined with a HMA shows the most promising results in this difficult-to-treat population.

Acute myeloid leukemia (AML) is a type of cancer of the bone marrow and blood that leads to overproduction of immature white blood cells. High-dose (intensive) chemotherapy is usually the first treatment option for AML. However, more than half of people newly diagnosed with AML cannot receive the recommended initial intensive chemotherapy due to older age or poor health. Treatment with low-dose cytarabine (LDAC) and hypomethylating agents (HMAs), such as azacitidine, is key for such people. We reviewed 26 clinical trials looking into available and developing treatment options for people who cannot have the recommended initial chemotherapy. The review found evidence that combining LDAC or HMA with a targeted therapy can improve survival. In AML, new therapies (such as ivosidenib, venetoclax and glasdegib) 'target' specific changes in the genes of cancer cells to slow or stop their division and growth. The greatest improvement in survival was seen in clinical trials where targeted therapies were added to azacitidine or LDAC. Targeted therapies may result in certain side effects that require regular monitoring. To provide patients with the benefits of targeted therapies they need to undergo genetic testing at the time of diagnosis. Tests to determine an individual's specific gene changes allows clinicians to develop personalised treatment plans with available targeted therapies. This shows promise in improving survival for people with AML who cannot receive initial intensive chemotherapy.

Cellulite Pathophysiology and Psychosocial Implications.

BACKGROUND: Cellulite is a highly prevalent aesthetic condition in postpubertal women. OBJECTIVE: The objective of this article was to describe the latest data on the pathophysiology of cellulite and to highlight the psychosocial aspects that should be considered when treating cellulite. METHODS: A roundtable meeting was convened to discuss and share views on the latest data on the pathophysiology and psychosocial aspects of cellulite. The participants' experience helped guide a narrative review on this topic. RESULTS: The pathophysiology of cellulite primarily involves fibrous septal changes. Strategies targeting the fibrous septa have shown the most consistent efficacy, while showing inconsistent or short-term results when targeting the other components of cellulite, such as decreased dermal thickness, vascular alterations, and inflammation. Female sex, increased age, and high body mass index contribute to cellulite pathophysiology. CONCLUSION: Patients seeking treatment for cellulite are willing to endure numerous treatments, high cost, temporary and/or delayed results, and invasive procedures with potential adverse effects. Psychological discomfort has been reported among patients with cellulite, and understanding their behaviors and psychological characteristics can help clinicians provide better care to these patients seeking treatment.

Fatal Meningitis and Sepsis Caused by Nontypeable Haemophilus influenzae.

The rates of nontypeable Haemophilus influenzae (NTHi) invasive disease have been increasing since the introduction of the Haemophilus influenzae type b (Hib) vaccine, but its significance in adults is unclear. A 33-year-old man with human immunodeficiency virus (HIV) was admitted for fever and acute confusion. The day prior to admission he presented to another emergency department for nausea, vomiting and diarrhea where he was thought to have food poisoning and was sent home. Ten days prior to admission, his primary physician thought his nasopharyngitis symptoms were due to the common cold. The patient's HIV had been controlled on antiretroviral therapy for the past 3 years; 1 month prior to admission his viral load was undetectable. Laboratory evaluation on admission was significant for elevated lactic acid and CD4+ cell count of less than 200. A head computed tomography (CT) was unremarkable, but a lumbar puncture was consistent with bacterial meningitis. Neisseria meningitidis was suspected and the patient was placed on empiric antibiotics. Shortly after admission the patient was intubated and suffered a cardiac arrest. The patient was placed on vasopressor support after circulation returned; a repeat head CT showed increased swelling of his brain. An electroencephalogram (EEG) indicated complete suppression of activity and the patient expired on day 2 of hospitalization. After the patient's death, cerebrospinal fluid (CSF) cultures reported as positive for Haemophilus influenzae (H. influenzae) and sent to the state lab where it was further classified as NTHi, biotype I. NTHi strains can cause invasive disease in adults and should be considered as a potential pathogen for meningitis and bacteremia.

Impact of distance education via interactive videoconferencing on students' course performance and satisfaction.

The impact of distance education via interactive videoconferencing on pharmacy students' performance in a course was assessed after implementation of a distance campus. Students filled out a "Student Demographic Survey" and a "Precourse Knowledge Assessment" at the start of the course and a "Postcourse Knowledge Assessment" and a "Postcourse Student Perceptions Survey" at the end of the course. The primary end point, a comparison of course grades (%) between the main and distance campuses, was examined using the two-sample t-test. We examined the relationships among demographics, campus location, course grades, grade point average, pre- and postcourse knowledge assessments, and postcourse perceptions as our secondary end points with parametric and nonparametric tests. Data from 93 students were included in the analysis [main campus ( n = 81); distance campus ( n = 12)]. Students on the main campus achieved a significantly higher final course grade (87 vs. 81%; P = 0.02). Scores on the Postcourse Knowledge Assessment were also significantly higher compared with those of students on the distance education campus (77 vs. 68%; P = 0.04). Students on both campuses reported self-perceived improvement in their knowledge base regarding various aspects of infectious diseases. Compared with the students on the distance campus, those on the main campus were more likely to subjectively perceive that they had succeeded in the course ( P = 0.04). Our study suggests that students on the main campus achieved a higher final course grade and were more likely to feel that they had succeeded in the course. Students on both campuses reported improvement in knowledge.

Drug updates and approvals: 2015 in review.

This article highlights important prescribing information for some drugs that received FDA approval within the past year. These include: atazanavir and cobicistat (Evotaz®), ceftazidime and avibactam (Avycaz®), edoxaban (Savaysa®), ivabradine (Corlanor®), liraglutide (rDNA origin) injection (Saxenda®), perindopril arginine and amlodipine besylate (Prestalia®), and secukinumab (Cosentyx®) subcutaneous injection.

Ombitasvir/paritaprevir/ritonavir and dasabuvir tablets for hepatitis C virus genotype 1 infection.

OBJECTIVE: To review the data with ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. DATA SOURCES: Phase I, II, and III trials and review articles were identified through MEDLINE (1996-January 2015) and PubMed (1996-January 2015), conference abstracts, and US national clinical trials registry, using the keywords NS3/4A protease inhibitor, NS5A inhibitor, NS5B polymerase inhibitor, ABT-450, ABT-267, ABT-333, paritaprevir, ombitasvir, and dasabuvir. STUDY SELECTION AND DATA EXTRACTION: Preclinical, phase I, II, and III studies describing pharmacology, pharmacokinetics, efficacy, safety, and tolerability were identified. DATA SYNTHESIS: Noncirrhotic patients with HCV genotype 1b experienced sustained virological response 12 weeks after completion of therapy (SVR12) rates of 96% to 100% when ombitasvir/paritaprevir/ritonavir and dasabuvir were administered for 12 weeks, regardless of inclusion of ribavirin. SVR12 rates of 95% to 97% were seen in noncirrhotic patients with HCV genotype 1a infection who received ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for 12 weeks. Patients with Child-Pugh Class A cirrhosis also experienced high SVR12 rates (91.8%) when ombitasvir/paritaprevir/ritonavir and dasabuvir were administered with ribavirin for 12 weeks. Cirrhotic patients with HCV genotype 1a and a history of prior null response to peginterferon/ribavirin have higher SVR12 rates when ombitasvir/paritaprevir/ritonavir and dasabuvir and ribavirin are administered for 24 instead of 12 weeks (94.2% vs 88.6%). Adverse events are typically mild, most commonly consisting of fatigue, headache, nausea, and diarrhea. CONCLUSION: The regimen consisting of ombitasvir/paritaprevir/ritonavir and dasabuvir is highly efficacious in the treatment of HCV genotype 1 infection, with minimal adverse events. It is expected to play an important role in the armamentarium of novel agents that have a high chance of curing HCV infection.

Sofosbuvir, a novel nucleotide analogue inhibitor used for the treatment of hepatitis C virus.

OBJECTIVE: To provide an overview of a novel anti-hepatitis C agent, sofosbuvir. KEY FINDINGS: Sofosbuvir is a novel nucleotide analogue inhibitor of hepatitis C virus (HCV) NS5B polymerase that has recently been approved by the Federal Drug Administration for the treatment of HCV genotypes 1, 2, 3 or 4 in a variety of patients. The emergence of such a novel treatment provides benefit to previously untreated genotypes and patient populations, with little chance of promoting significant viral resistance. Excellent sustained virologic response rates 12 weeks after the end of treatment (SVR12) were seen in phase II and III clinical trials when sofosbuvir was used with ribavirin. Even more promising are the results from phase II and III clinical trials that evaluated sofosbuvir in combination with other oral direct acting antivirals (DAAs). Data with sofosbuvir in the hepatitis C virus (HCV)/HIV coinfected and in the pre- and post-transplantation populations are still emerging. The drug was very well tolerated in clinical studies, with the most common adverse events of headache, nausea and fatigue. SUMMARY: Overall, sofosbuvir presents a new and effective treatment option for HCV-infected patients.

Successful treatment of infective panniculitis with daptomycin in a pregnant, morbidly obese patient.

OBJECTIVE: To report a case of infective panniculitis in a morbidly obese, pregnant woman, which was successfully treated with daptomycin. CASE SUMMARY: A 34-year-old, 27-week pregnant, morbidly obese woman with a history of skin/soft-tissue infections and diabetes mellitus, presented with panniculitis. Initial treatment with ß-lactam antibiotics did not result in clinical improvement. Methicillin-resistant Staphylococcus aureus was suspected, and 14 days of daptomycin 4 mg/kg (using total body weight) resulted in a clinical cure, without any adverse effects on the mother or the neonate. DISCUSSION: Panniculitis is a type of skin/soft-tissue infection that is often caused by Gram-positive microorganisms. Daptomycin is one of the recommended agents for the treatment of skin/soft-tissue infections in hospitalized patients; however, it has not been extensively studied in pregnancy or morbid obesity. Some data suggest that exposure to daptomycin is significantly increased in morbidly obese persons because of the higher total dose received in this patient population. Animal data suggest that this drug is safe in pregnancy (category B), and at the time of publication, 3 prior cases of safe use of daptomycin in pregnancy have been reported. CONCLUSIONS: This case provides additional evidence for the use of daptomycin in pregnancy as well as morbid obesity.

Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate single tablet for HIV-1 infection treatment.

OBJECTIVE: To review the clinical trials, pharmacologic characteristics, safety, and efficacy of the elvitegravir/cobicistat/emtricitabine/tenofovir single tablet formulation (Stribild). DATA SOURCES: Literature searches were performed in MEDLINE (1948-September 2012) and PubMed (1966-September 2012) using the search terms GS-9137, elvitegravir, GS 9350, cobicistat, quad pill, Stribild, and integrase inhibitors. Abstracts from HIV/AIDS conferences were reviewed. STUDY SELECTION AND DATA EXTRACTION: Phase 3 studies evaluating the safety and efficacy of Stribild were preferentially evaluated, as well as relevant references from the published studies. DATA SYNTHESIS: Stribild contains complete antiretroviral therapy for HIV-1 infection in a single tablet. It is the first once-daily therapy option available with an integrase inhibitor and a novel pharmacokinetic boosting agent. Stribild has shown noninferiority in viral load suppression at 48 weeks when compared with dual nucleoside/nucleotide reverse transcriptase inhibitor and either a ritonavir-boosted protease inhibitor or nonnucleoside reverse transcriptase inhibitor regimen. Stribild was well tolerated, but some patients experienced increases in serum creatinine early in treatment that stabilized over time. CONCLUSIONS: Stribild is the first single-tablet regimen for HIV-1 infection treatment containing an integrase inhibitor. It is expected to have a prominent place in the formularies of health plans providing care for individuals with HIV-1 infection.

Boceprevir: a novel NS3/4 protease inhibitor for the treatment of hepatitis C.

Hepatitis C virus (HCV) infection affects over 170 million people worldwide and is the most common blood-borne infection in the United States. Standard treatment with peginterferon alfa-ribavirin results in low sustained virologic response (SVR) rates in many patients, especially those who are African-American, are coinfected with human immunodeficiency virus (HIV), or have liver cirrhosis. Because of suboptimal SVR rates, new direct-acting antiviral agents that target HCV viral replication steps are in development. Boceprevir is one of the novel NS3/4A protease inhibitors that was recently approved by the U.S. Food and Drug Administration. We evaluated the literature regarding boceprevir by performing a MEDLINE search (January 1996-July 2011) to identify relevant clinical trials. Abstracts and poster and oral presentations from hepatology and HIV conferences were also reviewed. Potent anti-HCV activity was seen in clinical trials with boceprevir when it was studied in HCV genotype 1-infected patients who were naïve to or had experience with HCV therapy. Data with boceprevir in HIV-HCV-coinfected patients are currently lacking; however, initial data on drug-drug interactions between boceprevir and antiretrovirals have become available. Resistance to boceprevir has been evaluated in trials as well, although more data are needed in this area. The most common adverse events with boceprevir included anemia and dysgeusia. Based on available data, boceprevir is one of the promising novel direct-acting antiviral agents that will likely reshape the treatment of patients with HCV infection.

Telaprevir: a novel NS3/4 protease inhibitor for the treatment of hepatitis C.

Hepatitis C virus (HCV) infection affects millions of people worldwide; however, standard therapy with peginterferon and ribavirin has resulted in suboptimal responses. Thus, new anti-HCV drugs with novel mechanisms of action are being studied. In particular, new drugs are being developed that target the NS3/4A protease complex. We evaluated the literature on telaprevir, a new, oral, covalent, reversible NS3/4A HCV protease inhibitor. A MEDLINE search (January 1996-July 2011) was performed to identify relevant clinical trials, and abstracts from hepatology and human immunodeficiency virus (HIV) conferences were reviewed. In large clinical trials, the addition of telaprevir to peginterferon and ribavirin resulted in high sustained virologic response rates in both treatment-naïve and treatment-experienced patients infected with HCV genotype 1. Clinical data with telaprevir in the HIV-HCV coinfected population are emerging, as well as data on potential drug-drug interactions with this agent. Preliminary data describe the resistance profile of telaprevir; however, more information is needed in this evolving area. Telaprevir's most common adverse events included rash, pruritis, and anemia. Based on available data, this new anti-HCV drug will likely be widely used and may revolutionize the treatment of HCV-infected individuals.

Cenicriviroc, an orally active CCR5 antagonist for the potential treatment of HIV infection.

Treatment of HIV-1-infected individuals is often complicated by the development of antiretroviral resistance, and novel antiretroviral agents with unique mechanisms of action and resistance profiles are needed to address this issue. CCR5 inhibitors represent a new class of antiretroviral agents that block the CCR5 receptor and prevent HIV-1 recognition and entry into CD4+ macrophages and T-cells. Tobira Therapeutics Inc is developing cenicriviroc (TBR-652, formerly TAK-652), a potent inhibitor of CCR5-tropic HIV-1 replication. Cenicriviroc has good oral bioavailability, a long t1/2 that allows once-daily dosing, and has demonstrated excellent antiviral potency with minimal toxicity in in vitro studies and phase I clinical trials. Encouraging efficacy results have been reported from phase II clinical trials in patients with CCR5-tropic HIV-1. The drug is also an inhibitor of the CCR2 receptor, which is known to be associated with inflammatory-related disease states, leading to Tobira initiating a phase I clinical trial in patients with rheumatoid arthritis. Cenicriviroc is a promising CCR5 inhibitor with potentially important anti-inflammatory effects, and warrants further investigation.

IDX-899, an aryl phosphinate-indole non-nucleoside reverse transcriptase inhibitor for the potential treatment of HIV infection.

Antiretroviral drug resistance is one of the complications of highly active antiretroviral therapy (HAART). Second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) are being developed for use in patients infected with HIV-1 because of the enhanced activity of these inhibitors against viruses that are resistant to the first-generation NNRTIs. IDX-899 (GSK-2248761), under development by Idenix Pharmaceuticals Inc and ViiV Healthcare, is an aryl phosphinate-indole second-generation NNRTI that potently and selectively inhibits wild-type and NNRTI-resistant HIV-1 in vitro. Preclinical data for IDX-899 suggest a significantly greater barrier to resistance compared with that of the first-generation NNRTI efavirenz. Two pathways of resistance have been identified for IDX-899 in vitro that include Glu138Lys and Val90Ile/Tyr181Cys mutations. Pharmacokinetic studies demonstrated that IDX-899 exhibits linear, dose-proportional and food-dependent pharmacokinetics; Cmin concentrations achieved with this drug allow once-daily dosing. In phase I clinical trials, IDX-899 reduced HIV-1 RNA and increased CD4+ cell counts in treatment-naïve patients infected with HIV-1. At the time of publication, a phase II clinical trial of IDX-899 was being conducted.

Vicriviroc, a CCR5 receptor antagonist for the potential treatment of HIV infection.

Highly active antiretroviral therapy has revolutionized the care of patients with HIV infection, but treatment is often complicated by the development of antiretroviral resistance. CCR5 inhibitors are a novel class of antiretroviral agents that block the CCR5 receptor, thereby preventing HIV-1 recognition and entry into CD4+ macrophages and T-cells. Schering-Plough Corp is developing vicriviroc, a CCR5 inhibitor that has demonstrated good oral bioavailability, has a long half-life that allows once daily dosing, and is primarily metabolized by cytochrome P450 CYP3A4. In vitro and clinical data suggest that vicriviroc has excellent antiviral potency with minimal toxicity. Phase I and II clinical trials demonstrated promising efficacy results when vicriviroc is administered to patients infected with CCR5-tropic HIV-1. At the time of publication, phase III trials were ongoing or planned to investigate the efficacy and safety of vicriviroc in antiretroviral-naïve and -experienced patients infected with HIV-1.

Elvitegravir, an oral HIV integrase inhibitor, for the potential treatment of HIV infection.

The treatment of HIV is often complicated by the emergence of antiretroviral (ARV) resistance, which has prompted the development of ARV drugs with novel mechanisms of action and resistance profiles. One of the newest classes of ARVs is the integrase inhibitors. These agents inhibit viral replication by preventing integration of viral DNA into the host cell. Japan Tobacco Inc and Gilead Sciences Inc are developing elvitegravir, a novel integrase inhibitor undergoing phase III clinical trials. Elvitegravir is predominantly metabolized via cytochrome P450 (CYP)3A4, along with minor pathways including glucuronidation via UGT1A1/3 and oxidative metabolism. Consequently, the coadministration of elvitegravir with the protease inhibitor ritonavir (a substantial CYP3A4 inhibitor) results in significantly enhanced bioavailability and a longer half-life than with elvitegravir alone, allowing for the once-daily dosing of elvitegravir. In vitro and clinical data suggest that elvitegravir has an overlapping resistance profile with raltegravir and with other integrase inhibitors that are in development. Data from phase I/II clinical trials have demonstrated excellent virological responses with elvitegravir, as well as minimal toxicities. At the time of publication, phase III trials to examine the efficacy and toxicity of elvitegravir were enrolling patients infected with HIV-1.